Identifying the immune factors that protect against HIV-1 acquisition remains a top priority within the field. Examining subjects who are repeatedly exposed to HIV-1 but do not become infected (HESN) can be used to identify the correlates of protection. As opposed to injection drug use or sexual contact HESN cohorts, infants repeatedly exposed to virus from their mother's breast milk are ideal subjects because one has access to both samples from the exposed individual and the exposure virus. We hypothesize that antibodies present in an exposed infant influence the likelihood of maternal HIV-1 variants in establishing infection. Previous non- human primate studies strongly suggest that antibodies can help block virus transmission, but there is no direct human evidence that preexisting antibodies can block HIV-1 acquisition. In contrast to the passive immunization studies which use supra-physiologic levels of antibodies that can block cell-free challenge virus, infant infections may occur from cell-associated or cell-free variants in the breast milk that are may not be susceptible to the infant's pre-existing antibodies. We propose to test the hypothesis that infant antibodies that can specifically block the maternal variants protect against HIV-1 acquisition. In addition to finding correlations between the presence of antibodies and transmission during breast feeding, we will examine the mechanisms of protection. Antibodies may protect because they can neutralize a virus by preventing initial entry into a susceptible host cell. On the other hand, immune effector cells, such as natural killer cells, may eliminate maternal breast milk cell free viruses and infected cells through antibody dependent cellular cytotoxicity. Finally antibodies may prevent virus attachment to the gut homing receptor, ?4?7, which may prevent the virus from infecting susceptible cells destined to migrate to gut associated lymphoid tissue (GALT). Because after initial invasion, high level replication occurs within GALT, blocking the virus from reaching these important compartments may prevent the maternal variants from establishing a systemic infection within an exposed infant. Our proposed studies will provide the first direct evidence that pre-existing antibodies active against exposure viruses can prevent HIV-1 acquisition. In addition, our mechanistic studies will potentially inform the antibodies properties and specificities that should be elicited with vaccine immunogens. Our studies will have important implications for future HIV-1 vaccine efforts. PUBLIC HEALTH RELEVANCE: Identifying factors that protect against HIV-1 acquisition can be ideally identified by examining breast milk transmission among mother infant dyads because of availability of both the exposure virus and baby plasma. We hypothesize that antibodies that either neutralize the incoming virus, induce natural killer cell effector function or block migratin to the gut associated lymphoid tissue are important in protecting against HIV-1 acquisition. Showing that antibodies can decrease HIV-1 transmission and understanding the specific mechanisms for the protection will be important for future vaccine efforts.